Five subtypes of receptors have been cloned and characterized in the melanocortin family. These G-protein coupled receptors (GPCR) stimulate the cAMP signal transduction pathway in many different tissues, mediating a wide range of physiological functions. Melanocortin 1 receptor (MC1R) is mainly expressed in melanocytes, monocytes, and mast cells, to mediate pigmentation of the hair and skin and to block inflammation. MC2R is expressed in adipocytes and adrenal cells, to mediate steroidogenesis in the adrenal gland. MC3R is present in the brain, hypothalamus, heart, gut, and placenta, and has been associated with energy homeostasis and inflammation. MC4R is uniquely expressed in the brain, and controls feeding behavior, energy homeostasis, and erectile function. MC4R knock-out mice revealed the phenotype of hyperphasia and obesity. MC5R is found in a wide range of tissues and is considered to play a role for the exocrine gland system.
With a plethora of physiological functions of melanocortin receptors, a large number of compounds have been designed and synthesized in search for potent agonists and antagonists. Early examples are synthetic peptides and peptide analogues that have been identified on the basis of endogenous agonist such as MSH. These peptide agonists have been used to characterize the function of these receptors. NDP-MSH is a highly potent and nonselective agonist of MC1R, 3R, 4R and 5R, and has been reported to attenuate food intake and body weight gain in rat models. A cyclic heptapeptide MT-II is an agonist with a similar non-selective profile, and its therapeutic use has been proven in clinical trials for the treatment of erectile dysfunction.
Small molecule agonists for the melanocortin receptors have been reported to have significant activity in drug trials for the treatment of obesity, sexual dysfunction or inflammation. For example, a series of potent and selective MC4R agonists has been identified, one of which demonstrated significant effect for augmenting erectile response in mice (J. Med. Chem. 2002, 45, 4849). A number of MC4R agonists have also been identified, which displayed hyphophasic activity and anti-obesity effect in the rat model (Bioorg. Med. Chem. Lett. 2005, 15, 171, Bioorg. Med. Chem. Lett. 2005, 15, 3430, Bioorg. Med. Chem. Letu. 2005, 15, 3501). A highly potent and selective MC1R agonist has been discovered, which showed efficacy in an acute mouse model of inflammation (J. Med. Chem. 2003, 46, 1123). In addition, a variety of small molecules as MCR agonists have been described in the patent applications (WO 01/55109, WO 01/70337, WO 01/70708, WO 02/018327, WO 02/059095, WO 02/059107, WO 02/059117, WO 02/059108, WO 02/081443, WO 02/085925, WO 02/15909, WO 02/067869, WO 02/068387, WO 02/068388, WO 03/009847, WO 03/009850, WO 2004/087159, WO 2004/078716, WO 2004/078717, WO 2005/040109, WO 2005/047251, WO 2005/077935, WO 2005/077935, WO 2006/019787, WO 2006/020277, WO 2007/041052, WO 2007/041061, WO 2007/047496, WO 2006/072393, WO 2007/015157, WO 2007/015162).
In view of the unresolved deficiencies of the various pharmaceutical compounds as discussed above, there is continuing need in the art for small molecule MCR agonists and pharmacological compositions that have improved pharmacological profiles. It is, therefore, an object of the present invention to provide novel compounds that are useful for the treatment of obesity, diabetes, sexual dysfunction, and inflammation.